Uterine Sarcoma With EML4::NTRK3 Fusion: A Spectrum of Mesenchymal Neoplasms Harboring Actionable Gene Fusions.

NTRK gene fusions are part of a paradigm shift in oncology, arising as one of the main genomic alterations with actionability in the so-called "agnostic setting." In gynecologic pathology, the recent description of uterine sarcoma resembling fibrosarcoma and with NTRK rearrangements ( NTRK -rearranged uterine sarcoma) highlights the importance of recognizing clinicopathological cues that can lead to genomic profiling. Herein, we report the case of a 43-year-old woman presenting with vaginal bleeding and pelvic mass. Histopathology of the tumor showed moderately atypical spindle cells arranged in long fascicles reminiscent of fibrosarcoma, along with immunohistochemical positivity for S100, CD34, and pan-tropomyosin receptor kinase. This prompted RNA-sequencing and the finding of a rare EML4::NTRK3 fusion. Clinical, histologic, and molecular findings are described, in addition to discussions regarding differential diagnoses and possible implications of the findings in clinical practice.

Gingival metastasis of angiosarcoma of the breast as a first manifestation of spreading disease: Case report and review of the literature.

BACKGROUND: Angiosarcoma is an aggressive malignant neoplasm of vascular origin. Oral metastases of angiosarcoma are rare and have a non-specific clinical presentation, thus the diagnosis may be challenging. CASE REPORT: Herein we report a case of a 34-year-old female patient after treatment of a high-grade angiosarcoma of the breast, who presented an asymptomatic bleeding purplish nodule in the maxillary interdental papilla between the first and second premolar. A biopsy was performed, and the histological examination revealed infiltration by malignant neoplasm of epithelioid and fusocellular pattern. Immunohistochemical analysis demonstrated that neoplastic cells were positive for ERG and CD31, and negative for cytokeratins AE1/AE3, confirming the diagnosis of metastatic angiosarcoma. After investigation, multiple metastases were discovered. The patient is under management with chemotherapy and palliative radiotherapy for the bone lesions. CONCLUSION: Metastases should be considered in the differential diagnosis of oral lesions in patients with a previous history of cancer. Due to the morphology of angiosarcomas, the metastatic lesions may resemble benign vascular lesions, therefore, biopsy is mandatory to exclude malignancy.

NUT carcinoma, an under-recognized malignancy: a clinicopathologic and molecular series of 6 cases showing a subset of patients with better prognosis and a rare ZNF532::NUTM1 fusion.

NUT carcinoma (NC) is a rare malignancy with aggressive clinical behavior, defined by rearrangements involving the NUTM1 gene locus. This entity is often under-recognized and its diagnosis may be challenging. In this study, we describe a subset of patients that, despite the molecularly proven diagnosis of NC, show improved outcomes. In addition, we describe one case with the novel ZNF532::NUTM1 fusion. All cases of NC diagnosed from 2013 to 2022 in our department were retrieved. FISH using dual color bring-together probes and next-generation sequencing assay were performed to characterize the fusions involving NUTM1. Among 6 patients identified, 5 were men with a median age of 35.6 years. Four patients had primary tumors in the head and neck region (2 ethmoid sinus, 1 parotid gland, and 1 lacrimal gland); 1 in the mediastinum, and another presented with a femoral bone tumor. In all cases, the initial diagnoses were not NC. The cases showed different morphological patterns, including monomorphic, rhabdoid, and pleomorphic appearances. One case showed a pseudopapillary pattern. By immunohistochemistry, all tumors showed squamous differentiation and ≥50% of neoplastic cells with nuclear positivity for NUT antibody. One case expressed WT1 (C-terminus) and other showed chromogranin positivity. Genetic study revealed a BRD4::NUTM1 fusion in all head and neck cases, BRD3::NUTM1 in mediastinum case, and ZNF532::NUTM1 fusion in the femur bone case. They were treated with surgical resection plus chemotherapy and radiotherapy. The median overall survival was 23.11 months (1.6-83.3 months) and the median disease-free survival was 14.86 months (0-54.4 months). The patients with longer overall survival were one with a lacrimal gland primary (83.3 months) and other with a parotid lesion (31.9 months). Both patients were primarily treated with complete surgical resection. Anatomic location may be directly related to the overall survival in NC cases. Resectability of the lesion is also an important factor related to survival. Pathologists should include NC in the differential diagnosis of any poorly differentiated and undifferentiated monomorphic malignancy, regardless of its anatomic location.

Pleomorphic hyalinizing angiectatic tumor of the vulva: literature review based on a rare presentation.

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft tissues is a rare, non-metastatic tumor of unknown etiology and uncertain behavior, which may recur locally. There are few reports on this condition, and due to the rarity of the disease, its lineage has not yet been fully elucidated. The present study aims to report the case of an unusual entity observed for the first time in vulval topography. A female patient, 83 years old, presented with a tumor in the vulvar region that had evolved for approximately 4 months. Magnetic resonance imaging showed an expansive perineal formation of 8.5 × 3.5 cm, and a hemivulvectomy with a flap rotation was performed. The review of the slides revealed a mesenchymal lesion without significant atypia, which was richly vascularized. In the areas of interest, the immunohistochemical (IHC) study demonstrated positivity for CD34, estrogen, and progesterone receptors; it was negative for the other tested markers. Morphological findings associated with the IHC staining panel supported the diagnosis of PHAT. The main morphological features of PHAT are clusters of ectatic vessels of different sizes that show deposits of subendothelial and intraluminal fibrin. Fusiform and pleomorphic cells randomly arranged in leaves or long fascicles intermingle these vessels. It is essential to recognize this entity and consider it among the differential diagnoses of a mesenchymal lesion, given the wide variety of entities that comprise this group of lesions.

Pleomorphic hyalinizing angiectatic tumor of the vulva: literature review based on a rare presentation

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft tissues is a rare, non-metastatic tumor of unknown etiology and uncertain behavior, which may recur locally. There are few reports on this condition, and due to the rarity of the disease, its lineage has not yet been fully elucidated. The present study aims to report the case of an unusual entity observed for the first time in vulval topography. A female patient, 83 years old, presented with a tumor in the vulvar region that had evolved for approximately 4 months. Magnetic resonance imaging showed an expansive perineal formation of 8.5 × 3.5 cm, and a hemivulvectomy with a flap rotation was performed. The review of the slides revealed a mesenchymal lesion without significant atypia, which was richly vascularized. In the areas of interest, the immunohistochemical (IHC) study demonstrated positivity for CD34, estrogen, and progesterone receptors; it was negative for the other tested markers. Morphological findings associated with the IHC staining panel supported the diagnosis of PHAT. The main morphological features of PHAT are clusters of ectatic vessels of different sizes that show deposits of subendothelial and intraluminal fibrin. Fusiform and pleomorphic cells randomly arranged in leaves or long fascicles intermingle these vessels. It is essential to recognize this entity and consider it among the differential diagnoses of a mesenchymal lesion, given the wide variety of entities that comprise this group of lesions.

Neoadjuvant hypofractionated radiotherapy and chemotherapy for extremity soft tissue sarcomas: Safety, feasibility, and early oncologic outcomes of a phase 2 trial.

BACKGROUND AND PURPOSE: Optimal treatment of extremity soft tissue sarcomas (ESTS) is controversial. The aim of this study was to evaluate neoadjuvant chemotherapy (ChT) plus concomitant hypofractionated RT (hypo-RT) in local and distant disease relapse. Here we report safety, feasibility and early outcomes. MATERIALS AND METHODS: This was a prospective, single arm study with a goal accrual of 70 patients. Between 2015 and 2018, 18 patients with histologically confirmed nonmetastatic ESTS were assigned to receive doxorubicin and ifosfamide for three neoadjuvant cycles, concomitant with hypo-RT (25 Gy in 5 fractions) followed by surgery. The primary endpoint was disease-free survival (DFS). Secondary outcomes were pathologic response, wound complications (WC), and morbidity rates. RESULTS: Median follow-up was 29 months. At last follow-up, 13/18 patients were alive without evidence of local or systemic disease (DFS 72%), 1 had died due to metastatic disease, and 3 were alive with distant metastasis. One patient presented with local relapse within the irradiated field. Mean DFS time was 48.6 months (95% CI: 37.3-59.9). Six patients (33%) had no residual viable tumor detected in pathologic specimens (3 of these myxoid liposarcomas). There was a significant difference in WC among patients with acute RT skin toxicity. Six patients (33%) developed major WC. No grade 3 or 4 ChT adverse events were reported. CONCLUSION: Despite the limited sample size, these early outcomes demonstrate that this treatment regimen is feasible and well tolerated with high rates of limb preservation, local control, and pathologic complete response, supporting further investigation in a multi-institutional setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654.

Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Cellular angiofibroma of the vulva: case report with clinicopathological and immunohistochemistry study.

CONTEXT: Cellular angiofibroma of the vulva is a rare tumor that was first described in 1997. It occurs in middle-aged women (average age: 47 years), has small size (< 3 cm) and well-circumscribed margins. CASE REPORT: We describe a case in a 51-year-old woman whose preoperative diagnosis was confounded with Bartholin's glandular cyst. The neoplasia was well delimited and made up of three characteristic components: fusiform cells forming small fascicles, numerous blood vessels and adipose tissue interspersed between the fusiform cells. The stroma cells were positive for vimentin and negative for CD34, protein S-100, actin and desmin. The differential diagnoses for this tumor include aggressive angiomyxoma, angiomyofibroblastoma, lipoma of fusiform cells, solitary fibrous tumor, perineurioma and leiomyoma.

Cellular angiofibroma of the vulva: case report with clinicopathological and immunohistochemistry study

CONTEXTO: O angiofibroma celular da vulva é um tumor raro que foi inicialmente descrito em 1997. Ocorre em mulheres de meia-idade (média de idade: 47 anos), apresentar pequeno tamanho (< 3 cm) e margem bem circunscrita. RELATO DE CASO: Descrevemos um caso em mulher de 51 anos de idade cujo diagnóstico pré-operatório foi confundido com cisto de glândula de Bartholin. A neoplasia era bem delimitada e constituída por três componentes característicos: células fusiformes formando pequenos fascículos, numerosos vasos sangüíneos e tecido adiposo entremeado às células fusiformes. As células do estroma eram positivas para vimentina e negativas para CD34, proteína S-100, actina e desmina. O diagnóstico diferencial deste distinto tumor inclui angiomixoma agressivo, angiomiofibroblastoma, lipoma, tumor fibroso solitário, perineurioma, e leiomioma.